PROJECT SUMMARY Infants born preterm are known to have higher risks of developing adult lung diseases than those born full term. Prominent among these is an increased severity of illness following viral infection. The mechanism of this increased susceptibility is poorly understood. Much of the research to date has focused on the damage phase of the response to infection. With recent characterization of the progenitor cells that are central to influenza virus-induced repair, we hypothesize that compromised progenitor activity in the mature lungs of the former preterm population contribute to the increased severity of viral illness. In this proposal, we will determine how neonatal insults such as hyperoxia, which is routinely used to sustain life in preterm infants, leave a lasting impact on lung progenitors, compromising their ability to repair following influenza infection. We will use a mouse model of neonatal hyperoxia and adult influenza infection, which together recapitulate many of the changes as observed in human. We will address if the neonatal insult impacts the progenitor cells either directly (Aim 1), or indirectly through the mesenchymal cell microenvironment (Aim 2) or immune cell microenvironment (Aim 3). This proposal thereby addresses progenitor control by the microenvironment from a unique and clinically significant angle. We anticipate that our findings will reveal which progenitors and corresponding microenvironments are affected, how they are affected, and what are the key signals that mediate these changes.